11-67418944-C-G

Variant names:

• chr11-67418944-C-G
• rs372520034
• NM_001166222.2:c.553C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001166222.2(CARNS1):​c.553C>G​(p.Arg185Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000932 in 1,576,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R185W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000087 (0 hom.)
• Consequence: CARNS1 NM_001166222.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.70
• Publications: 1 publications found

Genes affected

CARNS1 (HGNC:29268): (carnosine synthase 1) CARNS1 (EC 6.3.2.11), a member of the ATP-grasp family of ATPases, catalyzes the formation of carnosine (beta-alanyl-L-histidine) and homocarnosine (gamma-aminobutyryl-L-histidine), which are found mainly in skeletal muscle and the central nervous system, respectively (Drozak et al., 2010 [PubMed 20097752]).[supplied by OMIM, Apr 2010]

PPP1CA (HGNC:9281): (protein phosphatase 1 catalytic subunit alpha) The protein encoded by this gene is one of the three catalytic subunits of protein phosphatase 1 (PP1). This broadly expressed gene encodes the alpha subunit of the PP1 complex that associates with over 200 regulatory proteins to form holoenzymes which dephosphorylate their biological targets with high specificity. PP1 is a serine/threonine specific protein phosphatase known to be involved in the regulation of a variety of cellular processes, such as cell division, glycogen metabolism, muscle contractility, protein synthesis, and HIV-1 viral transcription. Increased PP1 activity has been observed in the end stage of heart failure. Studies suggest that PP1 is an important regulator of cardiac function and that PP1 deregulation is implicated in diabetes and multiple types of cancer. Three alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2020]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021169543).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001166222.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARNS1	NM_001166222.2	MANE Select	c.553C>G	p.Arg185Gly	missense	Exon 5 of 10	NP_001159694.1	A5YM72-5
	CARNS1	NM_001394577.1		c.463C>G	p.Arg155Gly	missense	Exon 4 of 9	NP_001381506.1
	CARNS1	NM_001394578.1		c.184C>G	p.Arg62Gly	missense	Exon 4 of 9	NP_001381507.1	A5YM72-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARNS1	ENST00000687366.1	MANE Select	c.553C>G	p.Arg185Gly	missense	Exon 5 of 10	ENSP00000510668.1	A5YM72-5
	CARNS1	ENST00000307823.7	TSL:1	c.184C>G	p.Arg62Gly	missense	Exon 4 of 9	ENSP00000308268.3	A5YM72-1
	CARNS1	ENST00000445895.2	TSL:5	c.553C>G	p.Arg185Gly	missense	Exon 4 of 9	ENSP00000389009.2	A5YM72-5

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000150 AC: 28 AN: 186886 AF XY: 0.000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000389

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000178

Gnomad OTH exome AF: 0.000608

GnomAD4 exome AF: 0.0000870 AC: 124 AN: 1424676 Hom.: 0 Cov.: 32 AF XY: 0.0000907 AC XY: 64 AN XY: 705568

African (AFR) AF: 0.0000307 AC: 1 AN: 32550

American (AMR) AF: 0.000353 AC: 14 AN: 39628

Ashkenazi Jewish (ASJ) AF: 0.0000391 AC: 1 AN: 25554

East Asian (EAS) AF: 0.00 AC: 0 AN: 37520

South Asian (SAS) AF: 0.00 AC: 0 AN: 81876

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49554

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5728

European-Non Finnish (NFE) AF: 0.0000814 AC: 89 AN: 1093382

Other (OTH) AF: 0.000289 AC: 17 AN: 58884

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152310 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74482

African (AFR) AF: 0.0000481 AC: 2 AN: 41568

American (AMR) AF: 0.000523 AC: 8 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68018

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.000170

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000101 AC: 12

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	3.5
DANN	Benign	0.72
DEOGEN2	Benign	0.0053	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		-1.7
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.024
Sift	Benign	0.032	D
Sift4G	Benign	0.37	T
Polyphen		0.023	B
Vest4		0.14
MVP		0.081
MPC		0.14
ClinPred		0.016	T
GERP RS		-4.5
Varity_R		0.072
gMVP		0.32
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs372520034; hg19: chr11-67186415;